Chronic hypercapnia due to lung or neuromuscular disease or iatrogenic intervention is common in Veteran's Affairs patients. Permissive hypercapnia from low volume mechanical ventilation is standard care for protection against barotrauma in the lung, but the effects of chronic hypercapnia on the brain are largely unknown. Our goal is to understand the time course and molecular mechanisms of the central nervous system's response to chronic hypercapnia in order to extend and improve the quality of life in VA patients with chronic CO2 retention. Our central hypothesis is that chronic hypercapnia elicits adaptive and/or maladaptive neuroplasticity within the respiratory control network. Compensatory processes in the hippocampus depend on changes in glutamate receptor subunit (GluA, GluN) expression or activity state altering synaptic strength/network function. Other forms of neuroplasticity require changes in the serotonin (5-HT) system (TPH, SERT). Our studies on carotid body denervated (CBD) goats characterized effects of hypoventilation-induced hypercapnia on neurochemicals. Over 30 days after CBD, the expression of glutamate receptor subunits and markers of the 5-HT system were altered in respiratory-related and non-respiratory brainstem nuclei, indicating that hypercapnia per se contributed to these changes. Thus, we will test our central hypothesis by completing three Specific Aims (SA) on adult goats during both wakefulness and NREM sleep. SA 1 tests whether changes in glutamate receptor subunits and markers of the 5-HT system correlate with adaptive or maladaptive changes in ventilatory control during chronic hypercapnia. We hypothesize that over 30 days of increased inspired CO2 (InCO2) of 6% there will be: a) multiphasic changes in ventilation which will positively correlate with multiphasic changes in the activation state of GluA or GluN subunits within brainstem respiratory nuclei, b) a decrease over days in the ventilatory CO2 chemoreflex which will positively correlate with a decrease in markers of the 5-HT system, and c) a greater than normal difference in PaCO2, ventilation, and respiratory muscle activity between wakefulness and NREM sleep. Ventilation, arterial blood gases, and respiratory muscle activity (awake and asleep), and the CO2 chemoreflex (awake) will be measured before and during up to 30 days of chronic 6% CO2 exposure or 30 days of room air breathing. At 5, 15, and 30 days of chronic hypercapnia, 30 days of chronic normocapnia, and in an unoperated control group, goats will be euthanized and tissue punches from brainstem nuclei will be extracted for Western blot analyses of glutamate receptor subunits, 5-HT marker expression, and molecules that initiate neuroplasticity. SA 2 functionally tests if the adaptive/maladaptive changes in ventilatory control during chronic hypercapnia correlate with changes in glutamate receptor responsiveness within key sites that contribute to CO2 chemoreception and respiratory rhythm generation. We hypothesize that the hyperpnea during chronic increased InCO2, in awake goats will be attenuated by injection of a glutamate receptor antagonist into the retrotrapezoid nucleus (RTN) or preBtzinger Complex (preBtC), and the attenuation will positively correlate with the ventilation prior to injections. Microtubule (MT's) will be chronically implanted for injections of the glutamate receptor antagonist kynurenic acid (KynA) during increased InCO2 before, during, and 2-5 days after 30 days of chronic hypercapnia or 30 days of chronic normocapnia (control). SA 3 functionally tests if changes in ventilatory control during chronic hypercapnia correlate with changes in neuromodulators within the RTN or preBtC and/or are dependent upon 5-HT2A receptor neuromdoulation. We hypothesize InCO2 hypercapnia will decrease excitatory neuromodulators and the ventilatory response to a 5-HT2A receptor antagonist dialyzed into the RTN and preBtC. Through implanted MT's, mock cerebrospinal fluid will be dialyzed with or without antagonist before, during, and after 30 days of hypercapnia or normocapnia. Effluent dialyzed fluid will be analyzed for neuromodulator content.